CN113874001A

CN113874001A - Vitamin and mineral soft capsule formulation comprising vitamin C in the form of ascorbate

Info

Publication number: CN113874001A
Application number: CN202080036422.8A
Authority: CN
Inventors: J·祖梅塔佩雷斯; M·D·P·桑斯塞兹; M·A·卡巴罗冈萨雷斯; M·E·伊格莱西亚斯皮涅罗; R·特纳塞拉诺; L·蒙特斯欧唯雅诺; A·普莱尔卡瓦尼利亚斯
Original assignee: Bayer Consumer Care AG
Current assignee: Bayer Consumer Care AG
Priority date: 2019-05-22
Filing date: 2020-05-22
Publication date: 2021-12-31
Anticipated expiration: 2040-05-22
Also published as: UA128493C2; PH12021552923A1; US20230097996A1; WO2020234458A1; JP2022533731A; EP3972568A1; JP7536045B2; MX2021014231A; AR118962A1; CN113874001B; BR112021020965A2; EA202193169A1

Abstract

The present invention provides a composition, preferably a dietary or pharmaceutical composition, comprising or consisting of: vitamins (a) and optionally minerals (b) and pharmaceutically or dietetically suitable carriers such as the nutrients DHA and/or epa (C), encapsulated in soft gelatin such as bovine, porcine, vegetable and succinylated gelatin shells, wherein vitamins include vitamin C and said vitamin C is at least partially in the form of an ascorbate salt such as, but not limited to, calcium ascorbate or any other divalent cation salt such as magnesium ascorbate.

Description

Vitamin and mineral soft capsule formulation comprising vitamin C in the form of ascorbate

Technical Field

The invention relates to a medicine or diet unit dose soft capsule, which mainly comprises the following components: vitamins in which the ascorbic acid has been replaced by an ascorbate salt, preferably calcium ascorbate, and optionally a mineral compound and a pharmaceutically or dietetically suitable carrier, such as docosahexaenoic acid omega 3(DHA) and/or eicosapentaenoic acid omega 3 (EPA).

Background

Soft capsules are becoming more widely used, including prescription drugs, consumer health, vitamin and mineral supplements.

The process for manufacturing soft capsule products is carried out in five stages: preparation of the shell material, preparation of the filling material, encapsulation process, drying and finishing (see, for example, Hutchison KG, Ferdinando J. "Soft capsules". In: Aulton ME, Taylor KMG. Aulton's pharmaceuticals: the design and manufacture of the medicine. Elsevier Health Sciences 2013, page 597-.

Traditionally, the outer shell ("shell") is made of gelatin, plasticizer and water. Optional materials such as opacifiers, colorants, flavors, sweeteners, and preservatives may be included in the shell formulation. This material is formed into a shell that forms the outermost layer of the capsule and contains the fill material inside, which typically contains the API or nutrients and excipients ("fillers") for filling the shell itself.

One of the common challenges associated with soft capsule performance is capsule fragility, especially in soft capsule gelatin multivitamin/multimineral capsules. Capsule manufacturers often associate such poor performance of capsules with manufacturing processes or storage conditions. However, the ingredients of the shell or filler formulation may also play a role in this phenomenon.

The key to preventing brittleness is often related to maintaining optimal extensibility of the capsule shell, although other factors (e.g., fill pressure and impact during packaging, storage, and/or shipping) also play a role.

The elasticity and ductility of the shell material are generally related to the type of gelatin-origin, type of denaturing process, molecular weight, gel strength, type and amount of plasticizer, and content of pigments (e.g. content of titanium dioxide), wherein it is well known that high content of titanium dioxide is generally associated with higher risk of brittleness.

Furthermore, the elasticity and ductility of the shell material is also related to the moisture content of the capsule shell. In this sense and in a constant manner, the water of the shell formulation migrates from the shell material into the environment. The newly formed soft capsules on the packaging machine exhibit a moisture content of 35-40% (weight ratio; weight/weight). During drying, the air penetrates the shell, moving water outward to the surface of the soft gelatin capsules, reducing the initial moisture content to 20-25% (weight/weight) during first or dynamic drying and to 10-15% (weight/weight) during second or static drying (see, e.g., Gullapalli RP. Soft gels capsules (softgels). J Pharm Sci.2010; 99(10):4107-48), where the capsules tend to become brittle if they lose too much moisture (over-dry). This phenomenon also occurs during storage. To minimize moisture migration, the following factors may be optimized: such as gelatin aging during encapsulation, gelatin ribbon thickness and lubricants used, and further control of drying and storage conditions (temperature, humidity and air flow conditions). In fact, during the cold winter months, the heating system will dry the air to a relative humidity of 15% to 20%. It is disclosed that capsules exposed to such dry air lose moisture within minutes and become brittle. Under these conditions, portable industrial humidifiers can be used to maintain the relative humidity in the optimal range of 45% to 50%. The use of a resealable bag tie for an open capsule carton would make it easier for the operator to protect the capsule while inside the enclosure. Thus, it is apparent that manufacturing and storage conditions can affect the brittleness of the soft capsules.

In addition, free water of the shell formulation may migrate to the fill. The presence of hygroscopic compounds in the fill (absorbing moisture from the surroundings by absorption or adsorption) can promote embrittlement of the capsule by reducing the elasticity of the shell material or increasing the internal pressure. It is therefore important to recognize that formulation parameters also play an important role in overall capsule performance, including its tendency to become brittle.

In summary, many formulation parameters affect the mechanical properties of the raw materials and the capsule itself. Extensive experience is required in the capsule manufacturing field to determine the basic core characteristics that affect capsule performance. It is therefore important that the manufacturer also knows and closely checks these parameters to improve the performance of the soft capsules.

The technical problem faced by the present invention is to determine other formulation parameters that have a significant impact on the friability of soft gelatin capsules and solve this problem.

Drawings

FIG. 1 shows a schematic view of aThe figures illustrate the internal tests used in the examples to assess the friability of soft gelatin capsules. The method included placing each capsule on a metal test platform with the seam always parallel to the plate (fig. 1A). The methacrylate tube was placed in such a way that the capsule was centered in the tube (fig. 1B). The weight was placed on the platform and on top of it (fig. 1C), then the platform was opened to drop the weight onto the capsule (fig. 1D), and after the weight was dropped, the integrity of the capsule was checked (fig. 1E and 1F).

Detailed Description

The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the examples included therein.

As used herein, the term "pharmaceutical composition" refers to a composition that is suitable for use with prescription drugs and OTC drugs and is only available from a physician, pharmacy, or pharmacy.

As used herein, the term "dietary composition" refers to a composition that is used to supplement regular food intake with additional nutritional elements to improve quality of life, and that is freely available in grocery or supermarket stores without prescription, rather than just in drug stores.

As used herein, the pharmaceutical or dietary compositions are formulated in the form of soft gelatin capsules (softgel gelatin capsules).

The problem faced by the present invention is to identify the underlying root cause of the problem of widespread friability in soft gelatin multivitamin/multimineral capsules and to identify a solution to this problem.

Interestingly, as shown in example 1, friability tests carried out using standard multivitamin/multimineral formulations and different batches derived therefrom, either vitamin C free or containing vitamin C in ascorbic acid or ascorbate (e.g., calcium ascorbate) form, showed that the friability of these standard products can be avoided by removing vitamin C from the formulation or by replacing ascorbic acid with a source of vitamin C in ascorbate (e.g., calcium ascorbate) form. None of the other alternatives tested and shown in this example had a real and lasting effect on the brittleness of such compositions tested. Furthermore, any variation associated with shell formulation (type of gelatin, type of plasticizer and amount of plasticizer), packaging process parameters (gelatin ribbon thickness and type of lubricant) and drying conditions (air flow, temperature and humidity) solves the problem of brittleness of these products. Furthermore, the experiment carried out and detailed in example 2 of the present specification leads to the following conclusions: the removal of vitamin C in the form of ascorbic acid from the fill formulation of soft gelatin capsules avoids the brittleness problems associated with multivitamin derivative products. None of the other alternatives tested and shown in the examples had a real and lasting effect on the brittleness of such compositions tested.

Thus, the results provided herein demonstrate that ascorbic acid interacts with the other ingredients of the fill, weakening the shell and producing a frangible capsule. The use of vitamin C in the form of ascorbate minimizes these interactions, avoiding damage to the envelope and its attendant brittleness.

Accordingly, one aspect of the present invention provides a composition, preferably a dietary or pharmaceutical composition, comprising or consisting of: vitamins (a) and optionally minerals (b) and pharmaceutically or dietetically suitable carriers such as the nutrients DHA and/or epa (C), encapsulated in soft gelatin such as bovine, porcine, vegetable and succinylated gelatin shells, wherein vitamins include vitamin C and said vitamin C is at least partially in the form of an ascorbate salt such as, but not limited to, calcium ascorbate or any other divalent cation salt such as magnesium ascorbate.

In particular, a first aspect of the invention provides a composition, preferably a dietary or pharmaceutical composition, comprising or consisting of: vitamin (a) and optionally mineral (b) and a pharmaceutically or dietetically suitable carrier, such as the nutrients DHA and/or epa (C), encapsulated in soft gelatin, wherein the raw material for providing vitamin C in the final diet or pharmaceutical composition is in the form of an ascorbate salt, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate, and not in the form of ascorbic acid. In this sense it is noted that in the present invention the original source, raw material, for introducing vitamin C in the final dietary or pharmaceutical composition must at least partly be an ascorbate salt, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate. Preferably, the original source of vitamin C present in the final diet or pharmaceutical composition must be at least 10% (weight/weight) ascorbate, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate, wherein the weight percentage is calculated by determining the amount of ascorbate relative to the sum of the total amount of ascorbate and ascorbic acid present in the raw materials used to introduce the vitamin C present in the final diet or pharmaceutical composition. More preferably, the original source, raw material of vitamin C present in the final diet or pharmaceutical composition must be at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% (weight/weight) of ascorbate, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate, wherein these weight percentages are calculated by determining the amount of ascorbate relative to the sum of the total amount of ascorbate and ascorbic acid present in the raw material used to introduce the vitamin C present in the final diet or pharmaceutical composition. Still more preferably, the original source, raw material, used for introducing vitamin C in the final dietary or pharmaceutical composition is substantially pure, more than 80%, more preferably more than 90%, 95%, 96%, 97%, 98% or 99% pure ascorbate, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate.

Calcium ascorbate is a compound of the molecular formula CaC12H14O 12. It is the calcium salt of ascorbic acid, a mineral ascorbate. It has about 10 mass% calcium. As a food additive, its E number is E302. It is approved for use as a food additive in the european union, the united states and australia and new zealand.

Thus, the composition of the first aspect of the invention comprises vitamin C and may further comprise other vitamins, minerals or other types of nutrients as long as the raw materials used to produce the vitamin C present in the final diet or pharmaceutical composition, or the vitamin C present in the final diet or pharmaceutical composition, are substantially present in the form of ascorbate (as defined above), and wherein such diet or pharmaceutical composition may further consist of or comprise at least one of, or any mixture of: for example, vitamin a (i.e., retinol palmitate or beta-carotene), vitamin B1 (i.e., thiamine or thiamine nitrate), vitamin B2 (i.e., riboflavin), vitamin B3 (i.e., niacinamide), vitamin B5 (i.e., pantothenic acid or calcium pantothenate), vitamin B6 (i.e., pyridoxine or pyridoxine hydrochloride), vitamin B9 (i.e., folic acid or calcium methyltetrahydrofolate (Metafolin)), vitamin B12 (i.e., cyanocobalamin), vitamin H (i.e., biotin), vitamin D (i.e., vitamin D3), vitamin E (i.e., DL-alpha-tocopheryl acetate, DL-alpha-tocopherol or natural D-alpha-tocopherol), vitamin K, choline (i.e., choline bitartrate), iron (i.e., carbonyl iron, ferrous fumarate or ferrous sulfate), iodine (i.e., potassium or potassium iodide), magnesium iodate (i.e., magnesium oxide), zinc (i.e., zinc oxide or zinc sulfate), Selenium (i.e., sodium selenate), copper (i.e., copper oxide or copper sulfate), manganese (i.e., manganese sulfate), calcium (i.e., calcium phosphate or calcium carbonate), chromium (i.e., chromium chloride or chromium picolinate), molybdenum (i.e., sodium molybdate or ammonium molybdate), fluoride (i.e., calcium fluoride), chloride, potassium, sodium, DHA (i.e., DHA fish oil ethyl ester, DHA fish oil triglyceride, or DHA algae), and/or EPA (i.e., DHA fish oil ethyl ester, DHA fish oil triglyceride, or DHA algae). Such vitamins, minerals and other nutrients are commercially available from sources known to those skilled in the art.

Preferably, the dietary or pharmaceutical composition of the invention consists of or comprises the following: vitamin C in the form of an ascorbate salt, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate (as described above), and at least one other vitamin selected from vitamin a (e.g. beta-carotene), vitamin B1 (e.g. a thiamine salt), vitamin B2 (e.g. riboflavin), vitamin B3 (e.g. nicotinamide), vitamin B5 (e.g. pantothenate), vitamin B6 (e.g. pyridoxine salt), vitamin B12 (e.g. cyanocobalamin), vitamin D (e.g. cholecalciferol), vitamin E (e.g. alpha-tocopheryl acetate), vitamin B9 (e.g. folic acid or methyltetrahydrofolic acid (Metafolin acid)) and vitamin H (e.g. biotin), or any combination thereof.

Also preferably, the pharmaceutical or dietary composition according to the invention consists of or comprises the following: vitamin (a) selected from vitamin C in the form of ascorbate, such as, but not limited to, calcium ascorbate or any other salt of a divalent cation, such as magnesium ascorbate; and at least one other vitamin selected from vitamin a (e.g. retinol palmitate and beta-carotene), vitamin B1 (e.g. thiamine salts), vitamin B2 (e.g. riboflavin), vitamin B3 (e.g. niacinamide), vitamin B5 (e.g. pantothenate), vitamin B6 (e.g. pyridoxine salts), vitamin B12 (e.g. cyanocobalamin), vitamin D (e.g. cholecalciferol), vitamin E (e.g. DL-alpha-tocopherol acetate, DL-alpha-tocopherol or natural D-alpha-tocopherol), vitamin B9 (e.g. folic acid) and vitamin H (e.g. biotin), or any combination thereof.

In a further preferred embodiment of the first aspect of the invention, the pharmaceutical or dietary composition comprises one or more minerals or nutrients selected from at least one of the following: iron (e.g., ferrous fumarate), iodide (preferably potassium iodate), magnesium (preferably magnesium oxide), zinc (preferably zinc oxide), selenite (e.g., sodium selenite), and copper (preferably copper sulfate), or any combination thereof.

In another preferred embodiment of the first aspect of the invention, the pharmaceutical or dietary composition comprises a mineral selected from the group consisting of iron (as carbonyl iron), iodide (preferably potassium iodide), calcium (preferably calcium carbonate), magnesium (preferably magnesium oxide), zinc (preferably zinc oxide) and copper (preferably copper oxide), or any combination thereof.

More preferably, the dietary or pharmaceutical composition according to the invention comprises vitamin C in the form of an ascorbate salt, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate, and at least one other vitamin selected from vitamin a (e.g. beta-carotene), vitamin B1 (e.g. a thiamine salt), vitamin B2 (e.g. riboflavin), vitamin B3 (e.g. nicotinamide), vitamin B5 (e.g. pantothenate), vitamin B6 (e.g. pyridoxine salt), vitamin B12 (e.g. cyanocobalamin), vitamin D (e.g. cholecalciferol), vitamin E (e.g. alpha-tocopheryl acetate), vitamin B9 (e.g. folic acid or methyltetrahydrofolic acid), and vitamin H (e.g. biotin); and wherein such pharmaceutical or dietary compositions further comprise a mineral selected from iron (as ferrous fumarate), iodide (preferably potassium iodate), magnesium (preferably magnesium oxide), zinc (preferably zinc oxide), selenite (e.g., sodium selenite), and copper (preferably copper sulfate), or any combination thereof.

Still preferably, in another preferred embodiment of the first aspect of the present invention, the pharmaceutical or dietary composition consists of or comprises: vitamin (a) selected from vitamin C in the form of ascorbate, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate, and at least one other vitamin selected from the group consisting of: vitamin a (e.g., retinol palmitate and beta-carotene), vitamin B1 (e.g., thiamine salts), vitamin B2 (e.g., riboflavin), vitamin B3 (e.g., niacinamide), vitamin B5 (e.g., pantothenate), vitamin B6 (e.g., pyridoxine salts), vitamin B12 (e.g., cyanocobalamin), vitamin D (e.g., cholecalciferol), vitamin E (e.g., DL-alpha-tocopheryl acetate, DL-alpha-tocopherol, or natural D-alpha-tocopherol), vitamin B9 (e.g., folic acid), and vitamin H (e.g., biotin); and wherein such pharmaceutical or dietary compositions further comprise a mineral selected from the group consisting of: iron (as carbonyl iron), iodide (preferably potassium iodide), calcium (preferably calcium carbonate), magnesium (preferably magnesium oxide), zinc (e.g., zinc oxide), and copper (preferably copper sulfate and/or copper oxide), or any combination thereof.

Thus, various vitamins and minerals may be used in the dosage form of the present invention in varying amounts, which is preferably safe for anyone with mineral and/or vitamin deficiencies, such as, but not limited to, pregnant women, lactating women or women attempting to become pregnant with fertility potential, as long as the vitamins include vitamin C and the raw materials used to produce the vitamin C present in the diet or pharmaceutical composition, or the vitamin C present in the final diet or pharmaceutical composition is in the form of ascorbate, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate.

It should be noted that a variety of fats and oils may be used as carriers for the nutrients of the dietary or pharmaceutical compositions of the present invention. These fats or oils include, for example, olive oil, rapeseed oil, palm oil, coconut oil, sunflower oil, peanut oil, vegetable oils, lecithin, fish oil, cottonseed oil, soybean oil, lard, monoglycerides, diglycerides, butter, margarine, and other animal, vegetable, and marine fats, and milk fat, waxes such as beeswax, which are commercially available from sources known to those skilled in the art, and mixtures thereof. Vegetable oils are preferred fats for use in the food bar of the present invention. Preferably, DHA (docosahexaenoic acid omega) or EPA may be used. In addition, these compounds act as nutrients. DHA is a long chain fatty acid essential for brain and eye development in children and may comprise from about 10 to about 300 mg as a component of the dosage form of the present invention, with from about 100 to 200 mg being preferred, and about 150 mg being most preferred for pregnant women, lactating women, and women attempting to become pregnant with fertility potential.

Gelatin, on the other hand, is an essential component of the soft gelatin shells of the present invention. The starting gelatin material for the manufacture of soft capsules is obtained by partial hydrolysis of a raw gelatin material, such as the skin, white connective tissue or bone of an animal. According to the thermal denaturation process used to obtain collagen in the form of gelatin, gelatin materials can be classified as type a gelatin, which are obtained from the acid treatment of bovine bone, bovine hide and porcine skin and have isoelectric points between pH 7 and pH 9; and type B gelatin, which is obtained from alkali treatment of bovine bone and cow hide, and has isoelectric point between pH 4.7 and pH 5.2. Mixtures of type a and type B gelatins can be used to obtain a gelatin with the viscosity and gel strength characteristics required for capsule manufacture. Gelatin suitable for capsule manufacture is commercially available from Sigma Chemical Company of st louis, missouri. For a general description of gelatin and gelatin-based capsules, (see, e.g., Remington's Pharmaceutical Science, 16 th edition, Mack Publishing Company, Easton, Pa. (1980), pages 1245 and 1582 (1576-); and U.S. Pat. No. 4,935,243 to Borkan et al, 6/19/1990; both references are incorporated herein by reference in their entirety).

The soft gelatin shell of the capsule of the present invention as initially prepared comprises from about 20% to about 60% (w/w) gelatin, more preferably from about 25% to about 50% (w/w) gelatin, and most preferably from about 40% to about 50% (w/w) gelatin. The gelatin may be of type a and type B, or mixtures thereof, and has a bloom number of from about 60 to about 300.

The plasticizer is another component of the soft gelatin shell of the present invention. One or more plasticizers are incorporated to make a soft gelatin shell. The soft gelatin thus obtained has the flexibility characteristics required for use as an encapsulant. Plasticizers useful in the present invention include glycerin, sorbitan, sorbitol or similar low molecular weight polyols, and mixtures thereof.

The shell of the present invention, as initially prepared, typically comprises from about 10% to about 35% (w/w) plasticizer, preferably from about 15% to about 30% (w/w) plasticizer, and most preferably from about 20% to about 30% (w/w) plasticizer. A preferred plasticizer useful in the present invention is glycerin.

The soft gelatin shell of the present invention also comprises water. Without being bound by any theory, it is believed that water contributes to the rapid dissolution or rupture of the soft gelatin shell upon contact with gastrointestinal fluids encountered in the body.

The shell of the present invention, as initially prepared, typically comprises from about 15% to about 50% (w/w) water, more preferably from about 25% to about 40% (w/w) water, and most preferably from about 30% to about 40% (w/w) water.

Other optional components that may be incorporated into the soft gelatin shell include colorants (including colored coatings), flavors, preservatives, antioxidants, fragrances, and other aesthetic components.

The composition of the present invention can be encapsulated in any conventional soft gelatin shell capable of substantially containing the composition within a reasonable period of time. The soft gelatin shell of the present invention can be prepared by: appropriate amounts of gelatin, water, plasticizer and any optional components are combined in a suitable container and agitated and/or stirred while heating to about 65 ℃ until a homogeneous solution is obtained. Such soft gelatin shell formulations can then be packaged with the desired amount of the fill components using standard packaging methods to produce single-piece, air-tight, soft gelatin capsules. Gelatin capsules are formed into the desired shape and size for ease of swallowing. The soft gelatin capsules of the present invention are of suitable size for easy swallowing and typically contain from about 100mg to about 2000mg of the active ingredient. Soft gelatin capsules and packaging methods are described in P.K. Wilkinson et al, "Softgels: Manufacturing compositions", Drugs and the Pharmaceutical Sciences,41(Specialized Drug Delivery Systems), P.Tyle, codification (Marcel Dekker, Inc., New York,1990) page 409-; horns et al, "Capsules, Soft", Encyclopedia of Pharmaceutical Technology, Vol.2, J.Swarbrick and J.C.Boylan codification (Marcel Dekker, Inc., New York,1990) page 269-284; patel et al, "Advances in software Formulation Technology", Manufacturing chemistry, Vol.60, No. 7, pp.26-28(July 1989); patel et al, "Softgel Technology", Manufacturing Chemist, vol 60, No. 8, pages 47-49 (8 months 1989); jimers on, "Soft gel (Soft gel Capsule) Update", Drug Development and Industrial Pharmacy (Interphex'86Conference), Vol 12, No. 8&9, p 1133. 1144 (1986); and W.R.Ebert, "Soft Elastic gel Capsules: A Unit document Form", Pharmaceutical Technology, Vol.1, No. 5, pp.44-50 (1977); these references are incorporated herein by reference in their entirety. The obtained soft gelatin capsule is soluble in water and gastrointestinal fluid. After swallowing the capsule, the gelatin shell rapidly dissolves or breaks in the gastrointestinal tract, thereby introducing the pharmaceutically active substance from the liquid core into the physiological system.

Preferably, the capsule has an oblong or oval shape to facilitate swallowing. In the case of capsules containing 300 to 700mg of the combined active ingredients, the oval-shaped capsules may be about 10-28mm, preferably 20-26mm, in particular about 25mm long, and have a diameter of about 5 to 11mm, preferably 6-10mm, in particular 8-9 mm.

The composition of the invention may preferably comprise at least two, three, four, five or at least six nutrients selected from: iron (i.e., carbonyl iron, ferrous fumarate, or ferrous sulfate), iodide (i.e., potassium iodide or potassium iodate), magnesium (i.e., magnesium oxide), calcium (i.e., calcium carbonate), zinc (i.e., zinc oxide or zinc sulfate), copper selenite (i.e., copper sulfate or copper oxide), DHA, and EPA. Furthermore, the composition of the invention may preferably comprise at least two, three, four, five or at least six vitamins selected from the group consisting of: vitamin a (i.e. retinol palmitate or beta-carotene), vitamin B1 (i.e. thiamine or thiamine nitrate), vitamin B2 (i.e. riboflavin), vitamin B3 (i.e. niacinamide), vitamin B5 (e.g. pantothenic acid or calcium pantothenate), vitamin B6 (i.e. pyridoxine or pyridoxine hydrochloride), vitamin B9 (i.e. folic acid or calcium methyltetrahydrofolate), vitamin B12 (i.e. cyanocobalamin), vitamin H (i.e. biotin), vitamin D (i.e. vitamin D3), vitamin E (i.e. DL-alpha-tocopheryl acetate, DL-alpha-tocopherol or D-alpha-tocopherol), choline (i.e. choline tartrate) and vitamin K.

More particularly, the dietary or pharmaceutical composition of the invention comprises +/-200%, 150% or 100%, preferably +/-50%, more preferably +/-40%, 35%, 30%, 25%, 20%, 15%, 10%, 5% or 1% of the ingredients of the following formulae R21 and/or R22, in mg/capsule for the filler component and in weight percentages relative to the total components of the shell for the shell component:

TABLE 1 qualitative and quantitative composition of formulations R21 and R22

In another particular embodiment, the dietary or pharmaceutical composition of the invention comprises +/-200%, 150% or 100%, preferably +/-50%, more preferably +/-40%, 35%, 30%, 25%, 20%, 15%, 10%, 5% or 1% of the ingredients of each of the following formulations G3, G5, G7 or G8 (in mg/capsule for the fill component and in weight percent relative to the total components of the shell for the shell component):

TABLE 2 qualitative and quantitative composition of the formulations G3, G5, G7 and G8

Any of the dosage forms of the present invention, in addition to vitamin C which must be formulated in the form of an ascorbate salt, can be formulated, at least in part, using any of the pharmaceutically acceptable forms of vitamins and/or minerals (including their salts) described above as known to those skilled in the art. For example, useful pharmaceutically acceptable magnesium compounds include magnesium stearate, magnesium carbonate, magnesium oxide, magnesium hydroxide, and magnesium sulfate. Pharmaceutically acceptable iron compounds include any of the well known Ferrous (Ferrous) or ferric (ferric) supplements, such as Ferrous sulfate, ferric chloride, Ferrous gluconate, Ferrous lactate, Ferrous tartrate, iron-sugar-carboxylate complex, Ferrous fumarate, Ferrous succinate, Ferrous glutamate, Ferrous citrate, Ferrous pyrophosphate, Ferrous choline isocitrate (ferro cholinisonicite), Ferrous carbonate, and the like.

The vitamins and/or minerals used in the soft capsules of the present invention are those preferably recommended for consumption by anyone deficient in minerals and/or vitamins (such as, but not limited to, pregnant women, lactating women, or women with childbearing potential who are attempting to become pregnant). These vitamins and minerals are used in amounts effective to enhance the nutrition of a mineral and/or vitamin deficient person, such as, but not limited to, a pregnant woman, a lactating woman, or a woman with childbearing potential attempting to become pregnant, or a developing fetus or infant.

Each dosage form may contain one or more of the above vitamins, minerals or other nutrients in any amount that is safe for consumption by anyone lacking minerals and/or vitamins, such as, but not limited to, pregnant women, lactating women, or women with childbearing potential who are attempting to become pregnant (i.e., an amount that will not cause injury to the woman consuming the bar or to the fetus or infant in lactation that they are developing).

As mentioned above, it is preferred that the dosage form according to the invention essentially consists of: (a) vitamin complex mixtures consisting of batches (lots) based on formulations R21, R22, G3, G5, G7 or G8, which have calcium ascorbate in the filling to replace vitamin C in the form of ascorbic acid and are not considered brittle. It should be noted that such vitamin complex mixtures may be included with respect to these diets orAny one of the pharmaceutical compositions shownApproximatelyThe same qualitative and quantitative composition.

A second aspect of the invention relates to a method of supplementing the dietary needs of any person deficient in minerals and/or vitamins, such as but not limited to a pregnant woman, a lactating woman or a woman with childbearing potential attempting to become pregnant, said method comprising administering to the mineral and/or vitamin deficient person, such as but not limited to a dietary supplementing amount of a pharmaceutical or dietary composition of the first aspect of the invention. Preferably, the pharmaceutical or dietary composition is administered to a person deficient in minerals and/or vitamins in one unit dosage form per day.

A third aspect of the invention relates to a method of reducing the friability of a pharmaceutical or dietary composition in the form of a soft gelatin capsule consisting of or comprising: (a) one or more vitamins, wherein at least one of these vitamins is vitamin C in the form of ascorbic acid, and optionally (b) one or more minerals, and (C) a pharmaceutically or dietetically suitable carrier, such as DHA and/or EPA; wherein the method comprises replacing part or all of the content of vitamin C in the ascorbic acid form with vitamin C in the form of an ascorbate salt, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate.

Optionally, the third aspect of the invention further relates to a method of reducing the friability of a pharmaceutical or dietary composition in the form of a soft gelatin capsule consisting of or comprising: (a) one or more vitamins, wherein at least one of these vitamins is vitamin C in the form of ascorbic acid, and optionally (b) one or more minerals, and (C) a pharmaceutically or dietetically suitable carrier, such as DHA and/or EPA; wherein the method comprises reducing the partial or total content of vitamin C in the ascorbic acid form and replacing it with an ascorbate salt, such as, but not limited to, calcium ascorbate or any other divalent cation salt, such as magnesium ascorbate.

It should be noted that any of the vitamins, minerals and/or other nutrients indicated in the first aspect of the invention may also be present in the pharmaceutical or dietary composition indicated in the third aspect of the invention. In a preferred embodiment, the medicament or dietary composition shown in the third aspect of the present invention is a diet or pharmaceutical composition comprising vitamin C in the form of ascorbic acid, and at least one other vitamin selected from the group consisting of: vitamin a (e.g. beta-carotene), vitamin B1 (e.g. thiamine salts), vitamin B2 (e.g. riboflavin), vitamin B3 (e.g. niacinamide), vitamin B5 (e.g. pantothenate), vitamin B6 (e.g. pyridoxine salts), vitamin B12 (e.g. cyanocobalamin), vitamin D (e.g. cholecalciferol), vitamin E (e.g. alpha-tocopheryl acetate), vitamin B9 (e.g. folic acid or methyltetrahydrofolic acid), and vitamin H (e.g. biotin). Also preferably, the pharmaceutical or dietary composition shown in the third aspect of the present invention is a pharmaceutical or dietary composition comprising vitamin C in the form of ascorbic acid and at least one other vitamin selected from the group consisting of: vitamin a (i.e. retinol palmitate or beta-carotene), vitamin B1 (e.g. thiamine salts), vitamin B2 (e.g. riboflavin), vitamin B3 (e.g. niacinamide), vitamin B5 (e.g. pantothenate), vitamin B6 (e.g. pyridoxine salts), vitamin B12 (e.g. cyanocobalamin), vitamin D (e.g. cholecalciferol), vitamin E (e.g. DL-alpha-tocopheryl acetate, DL-alpha-tocopherol or natural D-alpha-tocopherol), vitamin B9 (e.g. folic acid) and vitamin H (e.g. biotin). Also preferably, the pharmaceutical or dietary composition shown in the third aspect of the present invention is a pharmaceutical or dietary composition comprising vitamin C in the form of ascorbic acid and at least one other vitamin selected from the group consisting of: vitamin a (e.g. beta-carotene), vitamin B1 (e.g. thiamine salts), vitamin B2 (e.g. riboflavin), vitamin B3 (e.g. niacinamide), vitamin B5 (e.g. pantothenate), vitamin B6 (e.g. pyridoxine salts), vitamin B12 (e.g. cyanocobalamin), vitamin D (e.g. cholecalciferol), vitamin E (e.g. alpha-tocopheryl acetate), vitamin B9 (e.g. folic acid or methyltetrahydrofolic acid), and vitamin H (e.g. biotin); and wherein such pharmaceutical or dietary compositions further comprise a mineral selected from the group consisting of: iron (such as ferrous fumarate), iodide (preferably potassium iodate), magnesium (preferably magnesium oxide), zinc (preferably zinc oxide), selenite (such as sodium selenite), and copper (preferably copper sulfate), or any combination thereof. Also preferably, the pharmaceutical or dietary composition shown in the third aspect of the present invention is a pharmaceutical or dietary composition comprising vitamin C in the form of ascorbic acid and at least one other vitamin selected from the group consisting of: vitamin a (such as retinol palmitate or beta-carotene), vitamin B1 (such as thiamine salts), vitamin B2 (such as riboflavin), vitamin B3 (such as niacinamide), vitamin B5 (such as pantothenate), vitamin B6 (such as pyridoxine salts), vitamin B12 (such as cyanocobalamin), vitamin D (such as cholecalciferol), vitamin E (such as DL-alpha-tocopheryl acetate, DL-alpha-tocopherol or D-alpha-tocopherol), vitamin B9 (such as folic acid), and vitamin H (such as biotin); and wherein such pharmaceutical or dietary compositions further comprise a mineral selected from the group consisting of: iron (e.g. carbonyl iron), iodide (preferably potassium iodide), calcium (preferably calcium carbonate), magnesium (preferably magnesium oxide), zinc (preferably zinc oxide) and copper (preferably copper sulphate and/or copper oxide), or any combination thereof.

A fourth aspect of the invention is a method of making or synthesizing a pharmaceutical or dietary composition according to the first aspect of the invention suitable for supplementing the dietary needs of any person deficient in minerals and/or vitamins, such as, but not limited to, pregnant women, lactating women or women attempting to become pregnant with fertility potential. Preferably, the formulation is used to prepare a single pharmaceutical or dietary unit dosage form that can be administered once daily.

Finally, it is contemplated that any of the features described herein may optionally be combined with any of the embodiments of any of the methods, medical uses, kits, and uses of kits of the present invention; and any of the embodiments discussed in this specification can be implemented with respect to any of them. It should be understood that the particular embodiments described herein are shown by way of example and not as limitations of the invention.

All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

The use of the terms "a" or "an" can mean "a" or "an", but it is also consistent with the meaning of "one or more," at least one, "and" one or more than one. The term "another" as used herein may also refer to one or more than one. The term "or" as used in the claims means "and/or" unless explicitly indicated to indicate only alternatives or alternatives are mutually exclusive.

As used in this specification and claims, the word "comprising" (and any form of comprising, such as "comprises" and "comprises"), "having" (and any form of having, such as "has and" has ")," including "(and any form of including, such as" includes or includes ") or" containing "(and any form of containing, such as" includes and includes ") is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. The term "comprising" also encompasses and explicitly discloses that the term "consisting of … …" and "consisting essentially of … …". As used herein, the phrase "consisting essentially of … …" limits the scope of the claims to particular materials or steps, as well as those materials or steps, that do not materially affect the basic and novel characteristics of the claimed invention. As used herein, the phrase "consisting of … …" excludes any element, step, or ingredient not specified in the claims except, for example, for impurities normally associated with that element or limitation.

As used herein, the term "or combinations thereof refers to all permutations and combinations of the terms listed prior to that term. For example, "A, B, C or a combination thereof" is intended to include at least one of a, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing this example, expressly included are combinations comprising repetitions of one or more items or terms, such as BB, AAA, AB, BBC, aaabccccc, CBBAAA, CABABB, and the like. Those skilled in the art will appreciate that there is generally no limitation on the number of items or terms in any combination, unless otherwise apparent from the context.

As used herein, approximating language, such as, but not limited to, "about," "approximately," refers to a condition that, when so modified, is not necessarily absolute or extremely accurate, but would nevertheless be recognized as sufficiently close to one of ordinary skill in the art to warrant designation of the condition as present. The extent to which the description may vary will depend on how much variation can be made and one of ordinary skill in the art will still recognize that the modified features still have the characteristics and capabilities required of the unmodified features. In general, but subject to the foregoing discussion, a numerical value modified herein by a approximating word (e.g., "about") may vary from the stated value by ± 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%. Thus, the term "about" may mean 5% of the indicated value, preferably 2% of the indicated value, most preferably the term "about" means exactly the indicated value (± 0%).

Examples

Example 1 evaluation of New formulations derived from vitamin Complex/mineral Complex Standard products (STD1 and STD2) Change of physical properties with time

The purpose of this example was to find out the likely root cause of the frangibility of the vitamin complex/mineral complex standard products STD1 and STD2, the qualitative and quantitative composition of each of which was determined in table 4 below.

In this sense, we note that we prepared such products according to the standard preparation method (STD) as described below:

-preparation of a filler formula:

the filling material is obtained by mixing oil and beeswax yellow at 60-65 deg.C. When all the beeswax yellow dissolved, the temperature was reduced to 45 ℃. Thereafter, minerals are added and mixed. In the second step, the temperature is lowered to 30 ℃ and the vitamin compound is added. The formulations are then mixed, homogenized, degassed and sieved. The mixture was stored in a closed tank with nitrogen before encapsulation.

-Preparation of Shell formulations

Gelatin blocks were obtained by mixing and melting in vacuum purified water, plasticizer, gelatin and colorant iron oxide.

-And (3) packaging:

the fill material and gelatin mass are processed into soft gelatin capsules using an encapsulation machine. The mixture of medium chain triglycerides and lecithin was used for lubricating the tape and as an anti-adhesive agent for the capsules.

-And (3) drying:

the obtained soft gelatin capsules were then dried. First dried using a rotary dryer. Final drying was carried out on trays into a static dryer.

We have also prepared such products by using different preparation methods. The reason for using different manufacturing processes is because it is known that by adjusting the encapsulation process parameters and controlling the drying and storage conditions, a reduction in the friability of the soft gelatin capsules can be achieved. In this sense, the following parameters relating to the standard preparation method were tested as shown in table 3 below:

-encapsulation process

Aging of gelatin: 12 hours and 72 hours

Thickness of gelatin band: 0.92, 0.95 and 1.00mm

Internal lubricants: mixture of medium chain triglycerides and lecithin or petrolatum

Drying process

Number of fans in the dynamic dryer that "turn on" airflow: 2 or 4 fans

Static drying conditions: 22 ℃/20% HR or 27 ℃/10% HR

In order to assess the friability of soft gelatin capsules produced by different methods, an internal test was developed. The method involves placing each capsule on a metal test platform with the seam always parallel to the plate (fig. 1A), where the position of the capsule is considered critical to the test as this position has a significant effect on the results. A methacrylate tube with an inner diameter of 30 mm, an outer diameter of 40 mm and a height of 100 mm was selected and placed with the capsule centered in the tube (fig. 1B). A 100g weight was placed on the platform and on top of it (fig. 1C), then the platform was opened to drop the weight onto the capsule (fig. 1D), and the integrity of the capsule was checked after the weight was dropped (fig. 1E and 1F).

A representative sample (25 capsules) was tested and the results expressed as a percentage of broken capsules. When the percentage of broken capsules exceeded 12%, the product was considered brittle.

TABLE 3 friability results for formulation STD and tests T1-T8 over a 3 month period.

From the above results, it is clear that the standard product, regardless of its preparation method, leads to the brittleness of the capsules (broken capsules. gtoreq.12%).

Thus, in addition to assessing the effect of different test methods on product friability, we further assessed the causes of this friability by preparing different qualitative and quantitative compositions derived from a multivitamin/complex mineral standard formulation (see compositions of formulations R1 to R22 in table 4 and table 5 below), including variations in shell and filler formulations.

In this respect, as described in the literature, the type of gelatin-origin, type of denaturing process, molecular weight, gel strength-influences the brittleness of the soft capsules. In addition, depending on the type and amount of plasticizer used, the brittleness phenomenon can be reduced.

On the other hand, we evaluated the effect of replacing different nutrients or excipients (which are found in the fill composition). In particular, we determined the presence or absence of magnesium oxide, tricalcium phosphate, glycerol (at various concentrations), lecithin, silica gel in the fill composition. We further evaluated the effect of replacing ascorbic acid with calcium ascorbate, zinc oxide for zinc sulfate, ferrous fumarate for ferrous sulfate, and changing the DHA oil type from DHA fish oil ethyl ester to DHA fish oil triglyceride. In addition, different amounts of beeswax were examined.

To meet the nutritional and size specifications for each capsule (13 rectangles), the fill weight of each capsule was adjusted according to the physical parameters of each fill formulation.

The different finished products were packed in polyethylene bags and stored under warehouse conditions (temperature between 15-25 ℃).

To find out the cause of brittleness, different batches (formulation STD and formulations R1-R22) were further tested for brittleness at different times (time 0, 1 month, 2 months, 3 months, 6 months, 9 months and 12 months). The results are expressed as a percentage of broken capsules and are summarized in table 6 below.

To assess the friability variable of each batch over time, the medium test in mod (Mood) (CI 95.0%) was used. The values obtained show that, in addition to the formulations R20, R21 and R22(p value >0.05), the brittleness of the different products increases significantly over time (p value. ltoreq.0.05).

For the R20 batch, the fill formulation did not contain any form of vitamin C, and 0% broken capsules were obtained at different sampling times tested. Thus, formulation R20 was not brittle after 12 months from the date of manufacture.

No significant difference was observed over time with respect to the friability results for formulations R21 and R22 (whose filler formulations contained vitamin C in the form of calcium ascorbate). Neither of these products exhibited brittleness problems after 12 months from the date of production.

Thus, vitamin C, which is ascorbic acid, is the root cause of the brittleness of the designed multivitamin/multimineral products (STD1 and STD 2). The use of vitamin C as calcium ascorbate allows the inclusion of vitamin C in the designed multivitamin/multimineral product without causing brittleness thereof.

Example 2. evaluation of the physical properties of the new batches G1 and G2 over time.

Two different formulations G1 and G2 were designed to achieve a complete vitamin complex/mineral complex prenatal supplement in one soft capsule (see table 7). Over time, friability problems were observed for both formulations (see table 8).

To determine the root cause of the friability of these compositions, the following modifications were made to make the six new formulations contained in table 7 (G3-G8).

-modification of the filler formulation:

changing ascorbic acid to calcium ascorbate;

changing copper sulfate to copper oxide; and

changing DL-alpha-tocopheryl acetate (synthetic vitamin E) to D-alpha-tocopherol (natural vitamin E)

Shell formulation was also modified:

change gelatin a to gelatin B.

In this respect, as described in the literature, the type of gelatin-origin, type of denaturing process, molecular weight, gel strength-affects the friable capsules. Thus, different gelatin types have been tested.

The fill weight of each capsule was adjusted in order to meet the labeling specifications for each nutrient per capsule and the standard size specification for the product (22 ovals).

The above batches of finished product were dried at 22 ℃ and 20% relative humidity. The drying process was stopped when the flexibility of the capsules reached 7.0N. Each different batch of capsules was packed in polyethylene bags and stored under warehouse conditions (temperature between 15-25 ℃).

To find out the cause of brittleness, different batches (formulations G1-G8) were further tested for brittleness at different times (time 0, 1 month, 2 months, 3 months and 6 months). The results are expressed as a percentage of broken capsules and are summarized in table 8 below.

To evaluate the friability variable of each batch over time, the medium test in mod (Mood) (CI 95.0%) was used. The values obtained show that the friability of the different products increases significantly with time (p value ≦ 0.05), and they retain less than 12% of the broken capsules during the stability process, except for formulations G3, G5, G7 and G8(p value > 0.05). A common factor in these formulations is the use of vitamin C such as calcium ascorbate.

Thus, the friability of the designed multivitamin/multimineral product is related to the type of vitamin C. Formulations containing calcium ascorbate were not considered brittle at 6 months. However, formulations containing ascorbic acid are considered brittle and their brittleness increases over time.

Claims

1. A pharmaceutical or dietary composition in the form of a soft gelatin capsule, comprising: (a) one or more vitamins, wherein the vitamins include vitamin C, and wherein the vitamin C is present in the form of at least 85% pure ascorbate , wherein the percentage is calculated by determining the amount of ascorbate relative to the sum of the total amount of ascorbate and ascorbic acid present in the composition; and optionally (b) one or more minerals; and (c) pharmaceutical Or a dietary suitable carrier such as the nutrients DHA or EPA.

2. A pharmaceutical or dietary composition in the form of a soft gelatin capsule consisting of: (a) one or more vitamins, wherein the vitamins include vitamin C; and optionally (b) one or more minerals and (c) a pharmaceutically or dietary suitable carrier, such as the nutrients DHA or EPA; wherein the raw material used to provide vitamin C present in the diet or in the pharmaceutical composition is at least 85% (w/w) ascorbate, wherein the weight percent is calculated by determining the amount of ascorbate relative to the sum of the total amount of ascorbate and ascorbic acid present in the raw material used to introduce vitamin C into the dietary or pharmaceutical composition.

3. The pharmaceutical or dietary composition according to claim 1 or 2, wherein the vitamin C is in the form of at least 90% pure ascorbate, or a raw material for providing vitamin C present in a diet or pharmaceutical composition At least 90% (w/w) ascorbate.

4. The pharmaceutical or dietary composition of claim 1 or 2, wherein the vitamin C is in the form of at least 95% pure ascorbate, or a raw material for providing vitamin C present in a diet or pharmaceutical composition At least 95% (w/w) ascorbate.

5. The pharmaceutical or dietary composition of any one of claims 1 to 4, wherein the ascorbic acid salt is a divalent cationic salt of ascorbic acid.

6. The pharmaceutical or dietary composition of claim 5, wherein the divalent cationic salt of ascorbic acid is calcium ascorbate.

7. The pharmaceutical or dietary composition of any one of claims 1 to 6, wherein the composition further comprises one or more vitamins selected from at least one of the following: vitamin A (i.e. retinol palmitate or beta-carotene), vitamin B1 (i.e. thiamine or thiamine nitrate), vitamin B2 (i.e. riboflavin), vitamin B3 (i.e. niacinamide), vitamin B5 (i.e. pantothenic acid or calcium pantothenate) , Vitamin B6 (i.e. pyridoxine or pyridoxine hydrochloride), vitamin B9 (i.e. folic acid or calcium methyltetrahydrofolate), vitamin B12 (i.e. cyanocobalamin), vitamin H (i.e. biotin), vitamin D (i.e. vitamin D3), vitamin E (ie, DL-alpha-tocopheryl acetate or natural and synthetic vitamin E), choline (ie, choline bitartrate), vitamin K, or any combination thereof.

8. The pharmaceutical or dietary composition of any one of claims 1 to 7, wherein the composition comprises one or more minerals selected from at least one of the following: iron (i.e. carbonyl iron, rich Ferrous maleate or ferrous sulfate), iodine (i.e. potassium iodide or potassium iodate), magnesium (i.e. magnesium oxide), calcium (i.e. calcium carbonate), zinc (i.e. zinc oxide or zinc sulfate), selenium (i.e. sodium selenate) ), copper (preferably copper sulfate or copper oxide), or any combination thereof.

9. The pharmaceutical or dietary composition of any one of claims 1 to 6, wherein the composition further comprises the following vitamins: vitamin A (eg beta-carotene), vitamin B1 (eg thiamine salts), Vitamin B2 (eg, riboflavin), vitamin B3 (eg, niacinamide), vitamin B5 (eg, pantothenate), vitamin B6 (eg, pyridoxine), vitamin B12 (eg, cyanocobalamin), vitamin D3 (eg, bile calciferol), vitamin E (DL-alpha-tocopheryl acetate), vitamin B9 (such as folic acid or methyltetrahydrofolate), and vitamin H (such as biotin); and wherein the composition further comprises the following minerals : iron (preferably ferrous fumarate), iodide (preferably potassium iodate), magnesium (preferably magnesium oxide), zinc (preferably zinc oxide), selenite (preferably sodium selenite) and copper (preferably copper sulfate).

10. The pharmaceutical or dietary composition of any one of claims 1 to 6, wherein the composition further comprises the following vitamins: vitamin A (eg retinyl palmitate or beta-carotene), vitamin B1 (eg thiamine salts), vitamin B2 (eg, riboflavin), vitamin B3 (eg, niacinamide), vitamin B5 (eg, pantothenate), vitamin B6 (eg, pyridoxine), vitamin B12 (eg, cyanocobalamin) ), vitamin D3 (such as cholecalciferol), vitamin E (DL-alpha-tocopheryl acetate or natural or synthetic vitamin E), vitamin B9 (such as folic acid), and vitamin H (such as biotin); and all of which The composition further comprises the following minerals: iron (preferably carbonyl iron), iodide (preferably potassium iodide), calcium (preferably calcium carbonate), magnesium (preferably magnesium oxide), zinc (preferably zinc oxide) and copper (preferably copper sulfate and/or copper oxide).

11. A pharmaceutical or dietary composition formulated into a soft gelatin capsule, wherein the capsule comprises a filler component and optionally a shell component, and wherein the ingredients (mg/capsule) for the filler component are selected from (the ±200% of indicated volume) any of the following formulas R21 or R22:

And optionally, wherein the ingredients for the shell composition (in weight percent relative to the total components of the shell) are selected from (±200% of the indicated amounts) any of the following formulations corresponding to formulations R21 or R22:

12. A pharmaceutical or dietary composition formulated as a soft gelatin capsule, wherein the capsule comprises a filler component and optionally a shell component, and wherein the ingredients (mg/capsule) for the filler component are selected from (the ±5% of indicated volume) any of the following formulas R21 or R22:

And optionally, wherein the ingredients for the shell composition (in weight percent relative to the total components of the shell) are selected from (±5% of the indicated amounts) any of the following formulations corresponding to formulations R21 or R22:

13. A pharmaceutical or dietary composition formulated as a soft gelatin capsule, wherein the capsule comprises a filler component and optionally a shell component, and wherein the ingredients (mg/capsule) for the filler component are selected from any of the following A formula R21 or R22:

And optionally, wherein the ingredients for the shell composition (in weight percent relative to the total components of the shell) are selected from any of the following formulations corresponding to formulations R21 or R22:

14. A pharmaceutical or dietary composition formulated as a soft gelatin capsule, wherein the capsule comprises a filler component and optionally a shell component, and wherein the ingredients (mg/capsule) for the filler component are selected from (the ±200% of indicated volume) any of the following formulations G3, G5, G7 or G8:

And optionally, wherein the ingredients used for the shell composition (in weight percent relative to the total components of the shell) are selected from (±200% of the indicated amounts) any of the following corresponding to formulations G3, G5, G7 or G8. A recipe:

15. A pharmaceutical or dietary composition formulated in the form of a soft gelatin capsule, wherein the capsule comprises a filler component and an optional shell component, and wherein the ingredients (mg/capsule) for the filler component are selected from (the ±5% of indicated volume) any of the following formulations G3, G5, G7 or G8:

and optionally, wherein the ingredients used for the shell composition (in weight percent relative to the total components of the shell) are selected from (±5% of the indicated amounts) below any of the formulations G3, G5, G7 or G8. A recipe:

16. A pharmaceutical or dietary composition formulated as a soft gelatin capsule, wherein the capsule comprises a filler component and optionally a shell component, and wherein the ingredients (mg/capsule) for the filler component are selected from any of the following A recipe G3, G5, G7 or G8:

And optionally, wherein the ingredients for the shell composition (in weight percent relative to the total components of the shell) are selected from any of the following formulations corresponding to formulations G3, G5, G7 or G8:

17. A method of reducing the friability of a pharmaceutical or dietary composition in the form of a soft gelatin capsule comprising (a) one or more vitamins, wherein at least one of these vitamins is vitamin C in the form of ascorbic acid, and any optionally (b) one or more minerals, and a pharmaceutically or dietary suitable carrier (c), such as DHA and/or EPA; wherein the method comprises substituting vitamin C in the form of ascorbate for vitamin C in the form of ascorbic acid part or all of the content.

18. A method of reducing the friability of a pharmaceutical or dietary composition in the form of a soft gelatin capsule, the capsule consisting of or comprising: (a) one or more vitamins, wherein at least one of these vitamins is in the form of ascorbic acid of vitamin C, and optionally (b) one or more minerals, and a pharmaceutically or dietary suitable carrier (c), such as DHA and/or EPA; wherein the method comprises reducing the amount of vitamin C in the form of ascorbic acid part or all of the content.

19. The method of claim 17 or 18, wherein the pharmaceutical or dietary composition is a dietary or pharmaceutical composition comprising vitamin C in the form of ascorbic acid and at least one other vitamin as claimed in claim 7; and any Optionally wherein the pharmaceutical or dietary composition further comprises at least one mineral of claim 8.

20. The method of claim 17 or 18, wherein the pharmaceutical or dietary composition is a dietary or pharmaceutical composition comprising vitamin C in the form of ascorbic acid and at least one other vitamin as claimed in claim 9 or 10; And optionally wherein the pharmaceutical or dietary composition further comprises at least one mineral as claimed in claim 9 or 10.

21. The pharmaceutical or dietary composition according to any one of claims 1 to 16 for supplementing the dietary needs of human subjects deficient in minerals, vitamins and/or other nutrients, such as pregnant women, lactating women or Women of reproductive potential trying to conceive (ie, amounts that will not cause harm to the woman consuming the bar or to her developing fetus or nursing infant).